OTHER ELECTROLYTESRegarding natremia, we observed a higher prevalence of both patients with hyperrnatremia and hyponatremia among positive subjects (table a in Supplementary Materials). Women tended to be more hypernatremic while men were more hyponatremic. However, these differences among groups were not statistically significant (table b in Supplementary Materials). At logistic regression, patients with SARS-CoV-2 infection had a slightly higher probability to presents to the ER with an alteration in natremia (OR 1.6, 95% CI 1.17-2.35 p<0.001). We detected also a mild tendency of infected patients to present with hypochloremia (table c Supple- mentary Materials) with no differences for sex and age groups (table d Supplementary Material). Lastly, nearly 30% of patients with SARS-CoV-2 infection presented to the ED with hypocalcemia versus 5.3% of negative subjects and only 0.4% were hypercalcemic among cases, compared to 7.4% of controls (table e Supplementary Materials). Differences among sex and age groups were visible with a lower prevalence of hypocalcemia among women compared to men, independently from infection status, and very significant differences between cases and controls for each of the six subgroups based on age group and sex. Prevalence of hypocalcemia among male patients with SARS-CoV-2 infection ranged from 28% to 34%, compared to 16% to 32% of females (table f in Supplementary Materials). At binary logistic regression the OR for being hypocalcemic if positive to SARS-CoV-2 was 7.2 (95% IC 4.8-10.6 p<0.0001) and at multivariable logistic regression women had a lower probability to have hypocalcemia (OR 0.63, 95% IC 0.4-0.8 p=0.005) (Figure 2) DISCUSSION In this cohort study, we evaluated the association between electrolyte imbalances and SARS- CoV-2 infection, deepening its distribution according to age and sex. To our knowledge, this is the first study conducted on a very large sample describing electrolytes alter- ations in patients infected with SARS-CoV-2 at admission to the ED and compared with a similar cohort of non-infected patients. Differently from the results reported by Chen et al. [10], we observed a lower prevalence of hypokalemic patients and a lower severity of hypokalemia. This is because we considered not only patients hospitalized for COVID-19, but a population of subjects positive to SARS-CoV-2 with a highly heterogeneous grade of the disease. Moreover, the novelty of this study lies in the description of the important and significant differences observed among female and male patients. Among women, the difference in the prevalence of hypokalemic patients between cases and controls tended to decrease with increasing age. This could be an expression of a different hormonal influence between pre- and postmenopausal women. This is supported by the influence of female sex hormones, mainly estrogens, on ACE2 which are able to impact the ACE/ACE2 activity ratio and the expression of angiotensin 1-7 [14, 15], also according to age [16]. Regarding calcium we observed a reverse trend, with higher prevalence of hypocalcemia among male patients; a trend is also observed in the non-positive population, but exacerbated by SARS-CoV-2 infection. As reported elsewhere [17], sex differences in hypocalcemia could be correlated to the more frequent use of vitamin D and/or calcium among women for osteoporosis prevention [18]. From a pathophysiological perspective SARS-CoV-2 is able to penetrate human cells by binding to ACE2 through a receptor binding domain present on the spike glycoprotein [19]. ACE2 is a receptor implied in the RAS system, in particular in the modulation of renal sodium transporters [20, 21], especially the Na+/K+ ATPase on the baso-lateral membrane of epithelial tubular cells [22, 23]. As explained in Figure 3, ACE2 cleaves angiotensin II in angiotensin 1-7, which is able to exert a natriuretic function by acting on the AT1 receptor. Furthemore, the action of ACE2 is also important to the vasodilation triggered by Ca++ release from the endoplasmic reticulum induced by angiotensin 1-7. The disruption of this pathway caused by the binding of SARS-CoV-2 on ACE2 could underlie the electrolytes alterations observed in this study and others as well [1, 8-10]. Indeed, recent studies reported evidences of kidney damage manifesting as tubular dysfunction and necrosis, endothelial alterations and deposition of complement complex on tubules [24, 25]. Electrolyte imbalances, especially of potassium and calcium, associated with SARS-CoV-2 infection could also help explain the numerous reports of QT prolongations, arrhythmias and cardiac deaths Sex differences in electrolyte imbalances caused by SARS-CoV2: a case-control study